Infectious diseases caused by pathogenic bacteria and viruses pose a serious challenge to global health. Each year ~2.9 million people die from AIDS, ~2 million from tuberculosis and 2 million from bacterially caused diarrhea. Emerging infectious pathogens like West Nile and Arena viruses pose new threats as they spread into previously unaffected areas around the globe. The possible emergence of a rapidly spreading avian flu strain H5N1 could lead to a devastating epidemic. Scientists at Yale University and other centers of excellence in the northeast are committed to the understanding of these diseases and the development of novel therapies. The study of the host- pathogen interactions in vitro has improved the molecular understanding of these diseases. Despite the increasing clarity in host-pathogen interactions, very little is known about the underlying mechanisms of how these diseases spread in vivo. The relevance of results gained in vitro in the absence of the vivo context is often limited. Here we propose the establishment of a state of the art two-photon imaging core facility housed under biosafety level three conditions (BSL3) for the visualization of host-pathogen interactions in living organisms. Intravital imaging will allow the visualization of the spreading of the infection and the immune responses as it happens in real time. Small animal models including the humanized mouse allow a faithful reconstruction of the human pathogenesis of these diseases. Newly available fluorescent labeling techniques make it possible to visualize individual pathogens including viruses and monitor their temporal and spatial spreading in the living organism. The imaging of infectious pathogens and the responding host immune cells in living organism is expected to revolutionize our understanding of disease pathogenesis and allow the rational design of novel therapies.